The present invention relates to mammalian telomerase genes and transcriptional regulatory regions thereof. The invention provides methods, cell lines, transgenic animals, and compositions relating to the fields of molecular biology, chemistry, pharmacology, and medical and diagnostic technology.
Telomerase is a ribonucleoprotein enzyme that synthesizes one strand of the telomeric DNA using as a template a sequence contained within the RNA component of the enzyme. See Blackburn (1992) Annu. Rev. Biochem. 61:113-129. Mammalian telomerase is composed of one or more protein components and an RNA component. The RNA component comprises a template repeat sequence complementary to the telomere repeat sequence. The RNA component of human telomerase ("HTR") has been reported (Feng et al. (1995) Science 269:1267, and the PCT publication Nos. 95/13381, published 18 May 1995; 95/13382, published 18 May 1995; 93/23572, published Nov. 25, 1993; and 96/01835, published 25 Jan., 1995 (incorporated herein in their entirety)).
Telomeres have an important biological role in maintaining chromosome structure and function. Current evidence is consistent with the idea that a loss of telomeric DNA acts as a trigger of cellular senescence and aging and that regulation of telomerase has important biological implications (see Harley (1991) Mutation Research 256:271). Telomerase activity has also been correlated with neoplastic transformation and cancer, wherein cancer cells characteristically exhibit telomerase activity. Most cancer cells or immortalized cell lines express high levels of telomerase activity, while in most normal somatic human cells, telomerase is not detected (Kim et al. (1994) Science 266:2011). Expression of antisense RNA complementary to hTR in an immortal human cancer cell line (HeLa) has been shown to induce cell crisis and cell death after a number of cell doublings (PCT patent publication No. 96/01835, published 25 Jan., 1996).
The transcriptional regulation of telomerase genes and factors or agents which can influence the expression of telomerase genes are not well-defined in the art. The development of transcriptional regulators which would afford a basis to control the expression of specific genes, such as telomerase genes, is a desired goal. Such transcriptional regulators can be pharmaceuticals for treating or preventing telomerase-related pathological conditions.
There is a great need in the art for methods and systems for identifying agents which regulate expression of mammalian telomerase. Significant improvements to and new opportunities for telomerase-mediated therapies and drug development methods could be realized if methods and systems for evaluating transcriptional effects of agents on expression of genes encoding the RNA component and/or encoding the protein components of telomerase were available.
The present invention meets these and other needs and provides such improvements and opportunities. The references discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the inventors are not entitled to antedate such disclosure by virtue of prior invention.